tbuckley/cabot-search huggingface dataset:
Therapeutic aptamer targeting sclerostin loop3 for promoting bone formation without increasing cardiovascular risk in osteogenesis imperfecta mice
Authors: Luyao Wang, Yuanyuan Yu, Shuaijian Ni, Dijie Li, Jin Liu, Duoli Xie, Hang Yin Chu, Qing Ren, Chuanxin Zhong, Ning Zhang, Nanxi Li, Meiheng Sun, Zong-Kang Zhang, Zhenjian Zhuo, Huarui Zhang, Shu Zhang, Mei Li, Weibo Xia, Zhenlin Zhang, Lin Chen, Peng Shang, Xiaohua Pan, Aiping Lu, Bao-Ting Zhang, Ge Zhang
Journal: Theranostics (2022)

Rationale: Sclerostin inhibition demonstrated bone anabolic potential in osteogenesis imperfecta (OI) mice, whereas humanized therapeutic sclerostin antibody romosozumab for postmenopausal osteoporosis imposed clinically severe cardiac ischemic events. Therefore, it is desirable to develop the next generation sclerostin inhibitors to promote bone formation without increasing cardiovascular risk for OI. Methods and Results: Our data showed that sclerostin suppressed inflammatory responses, prevented aortic aneurysm (AA) and atherosclerosis progression in hSOSTki.Col1a2+/G610C.ApoE-/- mice. Either loop2&3 deficiency or inhibition attenuated sclerostin's suppressive effects on expression of inflammatory cytokines and chemokines in vitro, whilst loop3 deficiency maintained the protective effect of sclerostin on cardiovascular system both in vitro and in vivo. Moreover, loop3 was critical for sclerostin's antagonistic effect on bone formation in Col1a2+/G610C mice. Accordingly, a sclerostin loop3-specific aptamer aptscl56 was identified by our lab. It could recognize both recombinant sclerostin and sclerostin in the serum of OI patients via targeting loop3. PEG40k conjugated aptscl56 (Apc001PE) demonstrated to promote bone formation, increase bone mass and improve bone microarchitecture integrity in Col1a2+/G610C mice via targeting loop3, while did not show influence in inflammatory response, AA and atherosclerosis progression in Col1a2+/G610C.ApoE-/- mice with Angiotensin II infusion. Further, Apc001PE had no influence in the protective effect of sclerostin on cardiovascular system in hSOSTki.Col1a2+/G610C.ApoE-/- mice, while it inhibited the antagonistic effect of sclerostin on bone formation in hSOSTki.Col1a2+/G610C mice via targeting loop3. Apc001PE was non-toxic to healthy rodents, even at ultrahigh dose. Apc001PE for OI was granted orphan drug designation by US-FDA in 2019 (DRU-2019-6966). Conclusion: Sclerostin loop3-specific aptamer Apc001PE promoted bone formation without increasing cardiovascular risk in OI mice.
Lipid phosphate phosphatase-2 promotes tumor growth through increased c-Myc expression
Authors: Xiaoyun Tang, Christopher R. Cromwell, Rongzong Liu, Roseline Godbout, Basil P. Hubbard, Todd P.W. McMullen, David N. Brindley
Journal: Theranostics (2022)

LPP2 is one of three enzymes in the lipid phosphate phosphatase family (LPP1-3) that dephosphorylate extracellular and intracellular bioactive lipid phosphates and pyrophosphates. LPP2 increases cell growth and LPP2 expression is elevated in a variety of malignancies, implying that LPP2 is a pro-tumorigenic factor. Methods: LPP2 expression in human breast tumors and normal breast tissue was measured by qPCR. To understand the role of LPP2, we knocked out its expression in multiple cell lines using CRISPR/Cas9. Cell proliferation and migration were compared between wild type and LPP2 knockout cells. Cell cycle was measured by flow cytometry, and cell cycle proteins were determined by western blotting. Effects of LPP2 on tumor growth were investigated using syngeneic and xenograft mouse breast cancer models. Results: LPP2 mRNA levels were higher in ER/PR positive, ER/HER2 positive, and triple negative human breast tumors, relative to normal breast tissue. Higher levels of LPP2 in breast tumors, hepatocellular carcinoma, pancreatic adenocarcinoma, and melanomas were prognostic of poorer survival. LPP2 mRNA expression is also increased in Hs-578T, MDA-MB-231, MCF7 and MDA-MB-468 breast cancer cell lines, relative to non-malignant Hs-578Bst, MCF10A and MCF-12A cells. LPP2 knockout in breast cancer cells decreased cell growth by inhibiting G1/S transition, whereas, increasing LPP2 levels in Hs-578Bst and MCF10A cells promoted proliferation. The effects of LPP2 on cell cycle were associated with changes in cyclin A2, cyclin B1, and cell cycle inhibitors, p27 or p21. The level of c-Myc was downregulated by knocking out LPP2, and it was partly restored by re-expressing LPP2. The positive correlation between the expression of LPP2 and c-Myc exists in multiple cancer cell lines including breast, lung, upper aerodigestive tract and urinary tract cancer. LPP2 knockout in MDA-MB-231 or 4T1 cells suppressed tumor formation in mouse breast cancer models, and decreased the in vivo expression of Ki67 and c-Myc of the cancer cells. Conclusion: Targeting LPP2 could provide a new strategy for decreasing c-Myc expression and tumor growth.
Conquering oncogenic KRAS and its bypass mechanisms
Authors: Pingping Hou, Y. Alan Wang
Journal: Theranostics (2022)

Aberrant activation of KRAS signaling is common in cancer, which has catalyzed heroic drug development efforts to target KRAS directly or its downstream signaling effectors.Recent works have yielded novel small molecule drugs with promising preclinical and clinical activities.Yet, no matter how a cancer is addicted to a specific target -cancer's genetic and biological plasticity fashions a variety of resistance mechanisms as a fait accompli, limiting clinical benefit of targeted interventions.Knowledge of these mechanisms may inform combination strategies to attack both oncogenic KRAS and subsequent bypass mechanisms.
Microbial metabolite restricts 5-fluorouracil-resistant colonic tumor progression by sensitizing drug transporters via regulation of FOXO3-FOXM1 axis
Authors: Sweta Ghosh, Rajbir Singh, Zachary Matthew Vanwinkle, Haixun Guo, Praveen Kumar Vemula, Ajay Goel, Bodduluri Haribabu, Venkatakrishna Rao Jala
Journal: Theranostics (2022)

The survival rate of colorectal cancer patients is adversely affected by the selection of tumors resistant to conventional anti-cancer drugs such as 5-fluorouracil (5FU).Although there is mounting evidence that commensal gut microbiota is essential for effective colon cancer treatment, the detailed molecular mechanisms and the role of gut microbial metabolites remain elusive.The goal of this study is to decipher the impact and mechanisms of gut microbial metabolite, urolithin A (UroA) and its structural analogue, UAS03 on reversal of 5FU-resistant (5FUR) colon cancers.Methods: We have utilized the SW480 and HCT-116 parental (5FU-sensitive) and 5FUR colon cancer cells to examine the chemosensitization effects of UroA or UAS03 by using both in vitro and in vivo models.The effects of mono (UroA/UAS03/5FU) and combinatorial therapy (UroA/UAS03 + 5FU) on cell proliferation, apoptosis, cell migration and invasion, regulation of epithelial mesenchymal transition (EMT) mediators, expression and activities of drug transporters, and their regulatory transcription factors were examined using molecular, cellular, immunological and flowcytometric methods.Further, the anti-tumor effects of mono/combination therapy (UroA or UAS03 or 5FU or UroA/UAS03 + 5FU) were examined using pre-clinical models of 5FUR-tumor xenografts in NRGS mice and azoxymethane (AOM)-dextran sodium sulfate (DSS)-induced colon tumors.Results: Our data showed that UroA or UAS03 in combination with 5FU significantly inhibited cell viability, proliferation, invasiveness as well as induced apoptosis of the 5FUR colon cancer cells compared to mono treatments.Mechanistically, UroA or UAS03 chemosensitized the 5FUR cancer cells by downregulating the expression and activities of drug transporters (MDR1, BCRP, MRP2 and MRP7) leading to a decrease in the efflux of 5FU.Further, our data suggested the UroA or UAS03 chemosensitized 5FUR cancer cells to 5FU treatment through regulating FOXO3-FOXM1 axis.Oral treatment with UroA or UAS03 in combination with low dose i.p. 5FU significantly reduced the growth of 5FUR-tumor xenografts in NRGS mice.Further, combination therapy significantly abrogated colonic tumors in AOM-DSS-induced colon tumors in mice.Conclusions: In summary, gut microbial metabolite UroA and its structural analogue UAS03 chemosensitized the 5FUR colon cancers for effective 5FU chemotherapy.This study provided the novel characteristics of gut microbial metabolites to have significant translational implications in drug-resistant cancer therapeutics.
Endoscopy International Open – recently published
Journal: Endoscopy (2019)

Comment on:Linked color imaging confers benefits in profiling H. pylori infection in the stomachEndosc Int Open 2019; 07(07): E885-E892DOI: 10.1055/a-0895-5377Comment on:Self-study of the non-extension sign in an e-learning program improves diagnostic accuracy of invasion depth of early gastric cancerEndosc Int Open 2019; 07(07): E871-E882DOI: 10.1055/a-0902-4467Comment on:Safety and efficacy of digital single-operator pancreatoscopy for obstructing pancreatic ductal stonesEndosc Int Open 2019; 07(07): E896-E903DOI: 10.1055/a-0889-7743
Effectiveness of wearable activity trackers to increase physical activity and improve health: a systematic review of systematic reviews and meta-analyses
Authors: Ty Ferguson, Timothy Olds, Rachel Curtis, Henry Blake, Alyson J Crozier, Kylie Dankiw, Dorothea Dumuid, Daiki Kasai, Edward O'Connor, Rosa Virgara, Carol Maher
Journal: The Lancet Digital Health (2022)

Wearable activity trackers offer an appealing, low-cost tool to address physical inactivity. This systematic review of systematic reviews and meta-analyses (umbrella review) aimed to examine the effectiveness of activity trackers for improving physical activity and related physiological and psychosocial outcomes in clinical and non-clinical populations. Seven databases (Embase, MEDLINE, Ovid Emcare, Scopus, SPORTDiscus, the Cochrane Library, and Web of Science) were searched from database inception to April 8, 2021. Systematic reviews of primary studies using activity trackers as interventions and reporting physical activity, physiological, or psychosocial outcomes were eligible for inclusion. In total, 39 systematic reviews and meta-analyses were identified, reporting results from 163 992 participants spanning all age groups, from both healthy and clinical populations. Taken together, the meta-analyses suggested activity trackers improved physical activity (standardised mean difference [SMD] 0·3–0·6), body composition (SMD 0·7–2·0), and fitness (SMD 0·3), equating to approximately 1800 extra steps per day, 40 min per day more walking, and reductions of approximately 1 kg in bodyweight. Effects for other physiological (blood pressure, cholesterol, and glycosylated haemoglobin) and psychosocial (quality of life and pain) outcomes were typically small and often non-significant. Activity trackers appear to be effective at increasing physical activity in a variety of age groups and clinical and non-clinical populations. The benefit is clinically important and is sustained over time. Based on the studies evaluated, there is sufficient evidence to recommend the use of activity trackers.
Bone morphogenetic protein 7 mediates stem cells migration and angiogenesis: therapeutic potential for endogenous pulp regeneration
Authors: Cheng Liang, Qingqing Liang, Xun Xu, Xiaojing Liu, Xin Gao, Maojiao Li, Jian Yang, Xiaotao Xing, Haisen Huang, Qi Tang, Li Liao, Weidong Tian
Journal: International Journal of Oral Science (2022)

Abstract Pulp loss is accompanied by the functional impairment of defense, sensory, and nutrition supply. The approach based on endogenous stem cells is a potential strategy for pulp regeneration. However, endogenous stem cell sources, exogenous regenerative signals, and neovascularization are major difficulties for pulp regeneration based on endogenous stem cells. Therefore, the purpose of our research is to seek an effective cytokines delivery strategy and bioactive materials to reestablish an ideal regenerative microenvironment for pulp regeneration. In in vitro study, we investigated the effects of Wnt3a, transforming growth factor-beta 1, and bone morphogenetic protein 7 (BMP7) on human dental pulp stem cells (h-DPSCs) and human umbilical vein endothelial cells. 2D and 3D culture systems based on collagen gel, matrigel, and gelatin methacryloyl were fabricated to evaluate the morphology and viability of h-DPSCs. In in vivo study, an ectopic nude mouse model and an in situ beagle dog model were established to investigate the possibility of pulp regeneration by implanting collagen gel loading BMP7. We concluded that BMP7 promoted the migration and odontogenic differentiation of h-DPSCs and vessel formation. Collagen gel maintained the cell adhesion, cell spreading, and cell viability of h-DPSCs in 2D or 3D culture. The transplantation of collagen gel loading BMP7 induced vascularized pulp-like tissue regeneration in vivo. The injectable approach based on collagen gel loading BMP7 might exert promising therapeutic application in endogenous pulp regeneration.
Systemic or Vaginal Hormone Therapy After Early Breast Cancer: A Danish Observational Cohort Study
Authors: Søren Cold, Frederik Cold, Maj-Britt Jensen, Deirdre Cronin-Fenton, Peer Christiansen, Bent Ejlertsen
Journal: JNCI Journal of the National Cancer Institute (2022)

Women treated for breast cancer (BC) often suffer genitourinary syndrome of menopause. These symptoms may be alleviated by vaginal estrogen therapy (VET) or menopausal hormone therapy (MHT). However, there are concerns of risks of recurrence of BC and death following treatment.Our study included longitudinal data from a national cohort of postmenopausal women, diagnosed 1997-2004 with early-stage invasive estrogen receptor-positive nonmetastatic BC, who received no treatment or 5 years of adjuvant endocrine therapy. We ascertained prescription data on hormone therapy, VET or MHT, from a national prescription registry. We evaluated mortality and risk of recurrence associated with use of VET and MHT vs non-use using multivariable models adjusted for potential confounders.Among 8461 women who had not received VET or MHT before BC diagnosis, 1957 and 133 used VET and MHT, respectively, after diagnosis. Median follow-up was 9.8 years for recurrence and 15.2 years for mortality. The adjusted relative risk of recurrence was 1.08 (95% confidence interval [CI] = 0.89 to 1.32) for VET (1.39 [95% CI = 1.04 to 1.85 in the subgroup receiving adjuvant aromatase inhibitors]) and 1.05 (95% CI = 0.62 to 1.78) for MHT. The adjusted hazard ratios for overall mortality were 0.78 (95% CI = 0.71 to 0.87) and 0.94 (95% CI = 0.70 to 1.26) for VET and MHT, respectively.In postmenopausal women treated for early-stage estrogen receptor-positive BC, neither VET nor MHT was associated with increased risk of recurrence or mortality. A subgroup analysis revealed an increased risk of recurrence, but not mortality, in patients receiving VET with adjuvant aromatase inhibitors.
Cardiac contractility modulation therapy improves health status in patients with heart failure with preserved ejection fraction: a pilot study (<scp>CCM‐HFpEF</scp>)
Authors: Cecilia Linde, Marcin Grabowski, Piotr Ponikowski, Ishu Rao, Angela Stagg, Carsten Tschöpe
Journal: European Journal of Heart Failure (2022)

This pilot study aimed to assess the potential benefits of cardiac contractility modulation (CCM) in patients with heart failure with preserved ejection fraction (HFpEF).This was a prospective, multicentre, single-arm, pilot study of CCM therapy in patients with HFpEF and New York Heart Association (NYHA) class II or III. Echocardiographic parameters were measured by an echo core laboratory to determine study eligibility. After CCM device implantation, patients were followed for 24 weeks. Overall, 47 patients (mean age 74.3 ± 4.4 years, 70.2% female) were enrolled, with left ventricular ejection fraction of 59 ± 4.4%, 63.8% with hypertension, 46.8% with atrial fibrillation, 40.4% with diabetes, 31.9% with at least one heart failure hospitalization in the prior year, 61.7% in NYHA class III, and Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary score of 48.9 ± 21.7. The primary efficacy endpoint (mean change in the KCCQ overall summary score) improved by 18.0 ± 16.6 points (p < 0.001) and there was an event-free rate of 93.6% for the primary safety endpoint (device- and procedure-related complications), as adjudicated by an independent physician committee.This pilot study demonstrates that the benefits of CCM may extend to the HFpEF patient population. The significant improvement in health status observed, with no obvious impact on safety, suggests that utilization of CCM for patients with HFpEF could prove to be promising.
A CMV-induced adaptive human Vδ1+ γδ T cell clone recognizes HLA-DR
Authors: Malte Deseke, Francesca Rampoldi, Inga Sandrock, Eva Borst, Heike Böning, George Liam Ssebyatika, Carina Jürgens, Nina Plückebaum, Maleen Beck, Ahmed Hassan, Likai Tan, Abdi Demera, Anika Janssen, Peter Steinberger, Christian Koenecke, Abel Viejo-Borbolla, Martin Messerle, Thomas Krey, Immo Prinz
Journal: The Journal of Experimental Medicine (2022)

The innate and adaptive roles of γδ T cells and their clonal γδ T cell receptors (TCRs) in immune responses are still unclear. Recent studies of γδ TCR repertoire dynamics showed massive expansion of individual Vδ1+ γδ T cell clones during viral infection. To judge whether such expansion is random or actually represents TCR-dependent adaptive immune responses, information about their cognate TCR ligands is required. Here, we used CRISPR/Cas9-mediated screening to identify HLA-DRA, RFXAP, RFX5, and CIITA as required for target cell recognition of a CMV-induced Vγ3Vδ1+ TCR, and further characterization revealed a direct interaction of this Vδ1+ TCR with the MHC II complex HLA-DR. Since MHC II is strongly upregulated by interferon-γ, these results suggest an inflammation-induced MHC-dependent immune response of γδ T cells.
Real-time echocardiography image analysis and quantification of cardiac indices
Authors: Ghada Zamzmi, Sivaramakrishnan Rajaraman, Li-Yueh Hsu, Vandana Sachdev, Sameer Antani
Journal: Medical Image Analysis (2022)

Deep learning has a huge potential to transform echocardiography in clinical practice and point of care ultrasound testing by providing real-time analysis of cardiac structure and function. Automated echocardiography analysis is benefited through use of machine learning for tasks such as image quality assessment, view classification, cardiac region segmentation, and quantification of diagnostic indices. By taking advantage of high-performing deep neural networks, we propose a novel and eicient real-time system for echocardiography analysis and quantification. Our system uses a self-supervised modality-specific representation trained using a publicly available large-scale dataset. The trained representation is used to enhance the learning of target echo tasks with relatively small datasets. We also present a novel Trilateral Attention Network (TaNet) for real-time cardiac region segmentation. The proposed network uses a module for region localization and three lightweight pathways for encoding rich low-level, textural, and high-level features. Feature embeddings from these individual pathways are then aggregated for cardiac region segmentation. This network is fine-tuned using a joint loss function and training strategy. We extensively evaluate the proposed system and its components, which are echo view retrieval, cardiac segmentation, and quantification, using four echocardiography datasets. Our experimental results show a consistent improvement in the performance of echocardiography analysis tasks with enhanced computational eiciency that charts a path toward its adoption in clinical practice. Specifically, our results show superior real-time performance in retrieving good quality echo from individual cardiac view, segmenting cardiac chambers with complex overlaps, and extracting cardiac indices that highly agree with the experts' values. The source code of our implementation can be found in the project's GitHub page.
Activating mTOR Mutations Are Detrimental in Nutrient-Poor Conditions
Authors: Agata A. Bielska, Caitlin F. Harrigan, Yeon Ju Kyung, Quaid Morris, Wilhelm Palm, Craig B. Thompson
Journal: Cancer Research (2022)

The mTOR is a key regulator of cell growth that integrates growth factor signaling and nutrient availability and is a downstream effector of oncogenic receptor tyrosine kinases (RTK) and PI3K/Akt signaling. Thus, activating mTOR mutations would be expected to enhance growth in many tumor types. However, tumor sequencing data have shown that mTOR mutations are enriched only in renal clear cell carcinoma, a clinically hypervascular tumor unlikely to be constrained by nutrient availability. To further define this cancer-type-specific restriction, we studied activating mutations in mTOR. All mTOR mutants tested enhanced growth in a cell-type agnostic manner under nutrient-replete conditions but were detrimental to cell survival in nutrient-poor conditions. Consistently, analysis of tumor data demonstrated that oncogenic mutations in the nutrient-sensing arm of the mTOR pathway display a similar phenotype and were exceedingly rare in human cancers of all types. Together, these data suggest that maintaining the ability to turn off mTOR signaling in response to changing nutrient availability is retained in most naturally occurring tumors.This study suggests that cells need to inactivate mTOR to survive nutrient stress, which could explain the rarity of mTOR mutations and the limited clinical activity of mTOR inhibitors in cancer.
CircGPR137B/miR-4739/FTO feedback loop suppresses tumorigenesis and metastasis of hepatocellular carcinoma
Authors: Lianyong Liu, Mingjun Gu, Junhua Ma, Ying Wang, Miao Li, Hui Wang, Xin Yin, Xiangqi Li
Journal: Molecular Cancer (2022)

Abstract Background Emerging evidence indicates that circular RNAs (circRNAs) and m 6 A RNA methylation participate in the pathogenesis and metastasis of multiple malignancies including hepatocellular carcinoma (HCC). However, it remains undocumented how circRNAs form a feedback loop with the m 6 A modification contributing to HCC. Methods A novel hsa_circ_0017114 (circGPR137B) was identified from three pairs of primary HCC and adjacent normal tissues by circRNA expression profiling. The association of circGPR137B and miR-4739 with clinicopathological parameters and prognosis in patients with HCC was analyzed by RT-qPCR, fluorescence in situ hybridization and TCGA cohorts. The role of circGPR137B in HCC was estimated in vitro and in vivo. RT-qPCR, western blot, m 6 A dot blot, RIP, MeRIP and dual-luciferase reporter assays were used to validate the reciprocal regulation of the feedback loop among circGPR137B, miR-4739 and m 6 A demethylase FTO. Meanwhile, the expression, function and prognosis of FTO in HCC were investigated by RT-qPCR, western blot, TCGA and rescue experiments. Results We identified a new dramatically downregulated circGPR137B in HCC tissues, and found that downregulation of circGPR137B or upregulation of miR-4739 was associated with poor prognosis in patients with HCC. Ectopic expression of circGPR137B strikingly repressed the proliferation, colony formation and invasion, whereas knockdown of circGPR137B harbored the opposite effects. Moreover, restored expression of circGPR137B inhibited tumor growth and lung metastasis in vivo. Further investigations showed that circGPR137B, co-localized with miR-4739 in the cytoplasm, acted as a sponge for miR-4739 to upregulate its target FTO, which mediated m 6 A demethylation of circGPR137B and promoted its expression. Thus, a feedback loop comprising circGPR137B/miR-4739/FTO axis was formed. FTO suppressed cell growth and indicated favorable survival in patients with HCC. Conclusion Our results demonstrate that circGPR137B inhibits HCC tumorigenesis and metastasis through the circGPR137B/miR-4739/FTO feedback loop. This positive feedback mechanism executed by functional coupling between a circRNA sponge and an m 6 A modification event suggests a model for epigenetics.